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Team Publications Controlling Microtubule Dynamics and Function with the Tubulin Code

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Team Publications Controlling Microtubule Dynamics and Function with the Tubulin Code Team Publications Controlling Microtubule Dynamics and Function with the tubulin code Year of publication 2009 Dorota Wloga, Danielle M Webster, Krzysztof Rogowski, Marie-Hélène Bré, Nicolette Levilliers, Maria Jerka-Dziadosz, Carsten Janke, Scott T Dougan, Jacek Gaertig (2009 Jun 15) TTLL3 Is a tubulin glycine ligase that regulates the assembly of cilia. Developmental cell : 867-76 : DOI : 10.1016/j.devcel.2009.04.008 Summary In most ciliated cell types, tubulin is modified by glycylation, a posttranslational modification of unknown function. We show that the TTLL3 proteins act as tubulin glycine ligases with chain-initiating activity. In Tetrahymena, deletion of TTLL3 shortened axonemes and increased their resistance to paclitaxel-mediated microtubule stabilization. In zebrafish, depletion of TTLL3 led to either shortening or loss of cilia in several organs, including the Kupffer’s vesicle and olfactory placode. We also show that, in vivo, glutamic acid and glycine ligases oppose each other, likely by competing for shared modification sites on tubulin. We propose that tubulin glycylation regulates the assembly and dynamics of axonemal microtubules and acts either directly or indirectly by inhibiting tubulin glutamylation. Krzysztof Rogowski, François Juge, Juliette van Dijk, Dorota Wloga, Jean-Marc Strub, Nicolette Levilliers, Daniel Thomas, Marie-Hélène Bré, Alain Van Dorsselaer, Jacek Gaertig, Carsten Janke (2009 Jun 12) Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation. Cell : 1076-87 : DOI : 10.1016/j.cell.2009.05.020 Summary Polyglycylation is a posttranslational modification that generates glycine side chains on proteins. Here we identify a family of evolutionarily conserved glycine ligases that modify tubulin using different enzymatic mechanisms. In mammals, two distinct enzyme types catalyze the initiation and elongation steps of polyglycylation, whereas Drosophila glycylases are bifunctional. We further show that the human elongating glycylase has lost enzymatic activity due to two amino acid changes, suggesting that the functions of protein glycylation could be sufficiently fulfilled by monoglycylation. Depletion of a glycylase in Drosophila using RNA interference results in adult flies with strongly decreased total glycylation levels and male sterility associated with defects in sperm individualization and axonemal maintenance. A more severe RNAi depletion is lethal at early developmental stages, indicating that protein glycylation is essential. Together with the observation that multiple proteins are glycylated, our functional data point towards a general role of glycylation in protein functions. Christoph Maas, Dorthe Belgardt, Han Kyu Lee, Frank F Heisler, Corinna Lappe-Siefke, Maria M Magiera, Juliette van Dijk, Torben J Hausrat, Carsten Janke, Matthias Kneussel (2009 May 26) INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Team Publications Controlling Microtubule Dynamics and Function with the tubulin code Synaptic activation modifies microtubules underlying transport of postsynaptic cargo. Proceedings of the National Academy of Sciences of the United States of America : 8731-6 : DOI : 10.1073/pnas.0812391106 Summary Synaptic plasticity, the ability of synapses to change in strength, requires alterations in synaptic molecule compositions over time, and synapses undergo selective modifications on stimulation. Molecular motors operate in sorting/transport of neuronal proteins; however, the targeting mechanisms that guide and direct cargo delivery remain elusive. We addressed the impact of synaptic transmission on the regulation of intracellular microtubule (MT)-based transport. We show that increased neuronal activity, as induced through GlyR activity blockade, facilitates tubulin polyglutamylation, a posttranslational modification thought to represent a molecular traffic sign for transport. Also, GlyR activity blockade alters the binding of the MT-associated protein MAP2 to MTs. By using the kinesin (KIF5) and the postsynaptic protein gephyrin as models, we show that such changes of MT tracks are accompanied by reduced motor protein mobility and cargo delivery into neurites. Notably, the observed neurite targeting deficits are prevented on functional depletion or gene expression knockdown of neuronal polyglutamylase. Our data suggest a previously undescribed concept of synaptic transmission regulating MT-dependent cargo delivery. Year of publication 2008 Peter Bieling, Stefanie Kandels-Lewis, Ivo A Telley, Juliette van Dijk, Carsten Janke, Thomas Surrey (2008 Dec 29) CLIP-170 tracks growing microtubule ends by dynamically recognizing composite EB1/tubulin-binding sites. The Journal of cell biology : 1223-33 : DOI : 10.1083/jcb.200809190 Summary The microtubule cytoskeleton is crucial for the internal organization of eukaryotic cells. Several microtubule-associated proteins link microtubules to subcellular structures. A subclass of these proteins, the plus end-binding proteins (+TIPs), selectively binds to the growing plus ends of microtubules. Here, we reconstitute a vertebrate plus end tracking system composed of the most prominent +TIPs, end-binding protein 1 (EB1) and CLIP-170, in vitro and dissect their end-tracking mechanism. We find that EB1 autonomously recognizes specific binding sites present at growing microtubule ends. In contrast, CLIP-170 does not end-track by itself but requires EB1. CLIP-170 recognizes and turns over rapidly on composite binding sites constituted by end-accumulated EB1 and tyrosinated alpha-tubulin. In contrast to its fission yeast orthologue Tip1, dynamic end tracking of CLIP-170 does not require the activity of a molecular motor. Our results demonstrate evolutionary diversity of the plus end recognition mechanism of CLIP-170 family members, whereas the autonomous end-tracking mechanism of EB family members is conserved. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Team Publications Controlling Microtubule Dynamics and Function with the tubulin code Carsten Janke, Krzysztof Rogowski, Juliette van Dijk (2008 Jul 1) Polyglutamylation: a fine-regulator of protein function? ‘Protein Modifications: beyond the usual suspects’ review series. EMBO reports : 636-41 : DOI : 10.1038/embor.2008.114 Summary Polyglutamylation is a post-translational modification in which glutamate side chains of variable lengths are formed on the modified protein. It is evolutionarily conserved from protists to mammals and its most prominent substrate is tubulin, the microtubule (MT) building block. Various polyglutamylation states of MTs can be distinguished within a single cell and they are also characteristic of specific cell types or organelles. Polyglutamylation has been proposed to be involved in the functional adaptation of MTs, as it occurs within the carboxy-terminal tubulin tails that participate directly in the binding of many structural and motor MT-associated proteins. The discovery of a new family of enzymes that catalyse this modification has brought new insight into the mechanism of polyglutamylation and now allows for direct functional studies of the role of tubulin polyglutamylation. Moreover, the recent identification of new substrates of polyglutamylation indicates that this post- translational modification could be a potential regulator of diverse cellular processes. Juliette van Dijk, Julie Miro, Jean-Marc Strub, Benjamin Lacroix, Alain van Dorsselaer, Bernard Edde, Carsten Janke (2008 Feb 15) Polyglutamylation is a post-translational modification with a broad range of substrates. The Journal of biological chemistry : 3915-22 : DOI : 10.1074/jbc.M705813200 Summary Polyglutamylation is a post-translational modification that generates lateral acidic side chains on proteins by sequential addition of glutamate amino acids. This modification was first discovered on tubulins, and it is important for several microtubule functions. Besides tubulins, only the nucleosome assembly proteins NAP1 and NAP2 have been shown to be polyglutamylated. Here, using a proteomic approach, we identify a large number of putative substrates for polyglutamylation in HeLa cells. By analyzing a selection of these putative substrates, we show that several of them can serve as in vitro substrates for two of the recently discovered polyglutamylases, TTLL4 and TTLL5. We further show that TTLL4 is the main polyglutamylase enzyme present in HeLa cells and that new substrates of polyglutamylation are indeed modified by TTLL4 in a cellular context. No clear consensus polyglutamylation site could be defined from the primary sequence of the here-identified new substrates of polyglutamylation. However, we demonstrate that glutamate-rich stretches are important for a protein to become polyglutamylated. Most of the newly identified substrates of polyglutamylation are nucleocytoplasmic shuttling proteins, including many chromatin-binding proteins. Our work reveals that polyglutamylation is a much more widespread post-translational modification than initially thought and thus that it might be a regulator of many cellular processes. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3 Team Publications Controlling Microtubule Dynamics and Function with the tubulin code Year of publication 2007 Juliette van Dijk, Krzysztof Rogowski, Julie Miro, Benjamin Lacroix, Bernard Eddé, Carsten Janke (2007 May 11) A targeted multienzyme mechanism for selective microtubule polyglutamylation. Molecular cell : 437-48 : DOI : 10.1016/j.molcel.2007.04.012 Summary Polyglutamylases are enzymes that
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